Local or systemic conditions can impair urogenital system function. Consider benign prostatic hyperplasia (BPH), which affects the walnut-sized prostate gland that surrounds the proximal urethra (the duct that drains the bladder). BPH commonly causes urinary tract symptoms secondary to bladder outlet obstruction. Bladder outlet obstruction has both a static component (structural and local) and a dynamic component (neurogenic and systemic). The static component is due to enlargement of the prostate gland, which commonly results in compression of the urethra and obstructed flow of urine from the bladder. The dynamic component is due to increased smooth muscle tone of the inner (involuntary) bladder neck sphincter. The dynamic component is at least partially regulated by alpha adrenergic sympathetic nervous system tone. Alpha adrenergic tone is mediated by way of alpha adrenergic synaptic receptors as well as by various second messenger pathways, including cyclic 3′-5′ adenosine monophosphate (cAMP). Smooth muscle tone of the inner sphincter may also depend on extra-and intracellular Ca2+ stores. Excessive inner sphincter smooth muscle tone results in bladder neck dysfunction.
Evaluation of BPH related urinary tract symptoms often includes use of an assessment test such as the International Prostate Symptom Score (I-PSS). A subject's I-PSS score is based on seven questions related to urination (incomplete emptying, frequency, intermittency, urgency, weak stream, straining, and nocturia). The nocturia question asks: “Over the past month, how many times did you most typically get up to urinate from the time you went to bed at night until the time you got up in the morning?” Patients with symptomatically significant BPH get up to urinate more times per night than is considered normal. Normal nocturnal urination frequency is zero or once. The symptom nocturia may also be considered to refer to difficulty initiating urine stream and complete bladder emptying during sleep hours.
Common treatments for BPH related urinary symptoms include administration of alpha adrenergic antagonists (alpha blockers) such as tamsulosin hydrochloride and terazosin hydrochloride. Alpha blockers decrease involuntary bladder sphincter tone of the prostatic urethra to promote free flow of urine and decreased urinary symptoms. Alpha blockers act on the dynamic component of bladder outlet obstruction. A common side effect of alpha blocker treatment is retrograde ejaculation.
Another common treatment for BPH related urinary symptoms acts on the static component of bladder outlet obstruction. It involves administration of the enzyme inhibitor finasteride. Finasteride is a competitive inhibitor of the enzyme 5areductase, which is responsible for the conversion of testosterone to dihydrotestosterone in the prostate gland. Dihydrotestosterone appears to be the major mitogen for prostate growth, and agents which inhibit 5a-reductase inhibit the progressive growth of the prostate which is characteristic of BPH. It thereby inhibits the progressive impairment of urine flow through the prostatic urethra with advancing age. Only men who already have significant prostate symptoms are likely to be treated with finasteride. Recognized side-effects of finasteride, experienced by around 6%-19% of users, include erectile dysfunction, and less often gynecomastia (breast gland enlargement).
The treatment of prostate symptoms as noted above are known to interfere with sexual functions such as penile erection and ejaculation. There are also physiologic interactions between the male reproductive and urinary systems. For example, it is normally not possible for males to voluntarily urinate while having an erection. Analogously it may be that nocturnal erections serve to prevent involuntary nocturnal bladder emptying. Both BPH and erectile dysfunction occur with increasing frequency over the age of fifty in men. It is not established whether there is a causal connection between these two common urogenital disorders of aging men. Various exemplary compounds, compositions and methods described herein aim to address urinary system and/or male reproductive system health and disorders. They may also address certain urinary system disorders in females.